Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017)

J Med Chem. 2012 Jun 28;55(12):5951-64. doi: 10.1021/jm300592r. Epub 2012 Jun 19.

Abstract

Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Administration, Oral
  • Animals
  • Biological Availability
  • Dogs
  • Drug Discovery*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Models, Molecular
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Niacinamide / pharmacokinetics
  • Niacinamide / pharmacology
  • Piperidines / administration & dosage
  • Piperidines / metabolism
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology*
  • Protein Conformation
  • Rats
  • Substrate Specificity

Substances

  • 2-(1-(5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl)-3-piperidyl)acetic acid
  • Enzyme Inhibitors
  • Piperidines
  • Niacinamide
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1